Autoimmune, respiratory and inflammatory diseases such as rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE), chronic obstructive pulmonary disease (COPD), and asthma are chronic and often progressive diseases associated with a dysregulated or overactive immune system. The causes and the drivers of these diseases remain ill-defined. They are characterized by complex cellular interactions between multiple inflammatory cells of the innate and adaptive immune system. Accordingly, the heterogeneity and complexity of the disease etiology of these conditions makes the search for new cellular targets challenging, as it is unclear who in the cellular infiltrate is a primary player of the pathology versus an “innocent” bystander.
Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disease characterized by chronic inflammation of multiple joints with associated systemic symptoms such as fatigue. This inflammation causes joint pain, stiffness and swelling, resulting in loss of joint function due to destruction of the bone and cartilage, often leading to progressive disability. Patients with RA also have an increased likelihood of developing other systemic complications such as osteoporosis, anaemia, and other disorders affecting the lungs and skin. The disease also impacts on the average life expectancy, shortening it by three to seven years.
There are a number of treatments available to manage RA. Some address the signs and symptoms of RA, others aim to modify the course of the disease and positively impact the systemic effects of RA, such as fatigue and anaemia.
The current treatments include use of:
Biologics: These are genetically-engineered drugs that target specific cell surface markers or messenger substances in the immune system called cytokines, which are produced by cells in order to regulate other cells during an inflammatory response. An example of a specific cytokine targeted by biologics is tumor necrosis factor alpha (TNFα).
Traditional disease-modifying anti-rheumatic drugs (DMARDs): These are non-specific immunosuppressive drugs, intended to combat the signs and symptoms of RA as well as slowing down progressive joint destruction. These treatments are often used in combination with one another, or in combination with a biologic agent, to improve patient response.
Glucocorticoids (corticosteroids): These are anti-inflammatory drugs related to cortisol, a steroid produced naturally in the body, that work by countering inflammation. However, the side-effects of glucocorticoids, which include hyperglycaemia, osteoporosis, hypertension, weight gain, cataracts, sleep problems, muscle loss, and susceptibility to infections, limit their use.
Non-steroidal anti-inflammatory drugs (NSAIDs): These manage the signs and symptoms of RA, such as reducing pain, swelling, and inflammation, but do not alter the course of the disease or slow the progression of joint destruction.
There are also a number of RA therapies targeting other components of the immune system. These include biologic treatments targeting alternative cytokines such as interleukin-6 (IL-6) that help to reduce inflammation and the progression of RA in the joints and throughout the body.
Asthma is the most common chronic disease among children and also affects millions of adults. Some 235 million people worldwide suffer from this disease. The causes of asthma, however, are not well understood.
Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition and a major cause of morbidity and mortality worldwide. As the disease progresses, patients with COPD may become prone to frequent exacerbations, resulting in patient anxiety, worsening health status, lung function decline, and increase in mortality rate. These episodes of worsening respiratory function lead to increases in health care utilization, hospital admissions and costs. Worse, frequent exacerbations are associated with a faster decline in lung function, thereby shortening life expectancy.
According to the recommendations of Global Initiative for Chronic Obstructive Lung Disease (GOLD), the first line therapy for COPD are long acting β-agonists, long acting muscarinic antagonist and inhalation corticosteroids. However, these drugs reduce the symptoms and exacerbations associated with the disease, rather than targeting its molecular and cellular basis. Accordingly, there is still a need for further improvement of COPD therapy.
Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3 position hydroxyl group of the inositol ring of phosphoinositide lipids (PIs) generating lipid second messengers. There are four claim I PI3K isoforms—alpha, beta, delta, and gamma.
IC87114 (2-((6-amino-9H-purin-9-yl) methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one) is a specific PI3Kδ inhibitor (Sadhu, J. Immunology, 1; 170(5):2647-2654, 2003; International Publication No. WO 2010/111432 and U.S. Publication Nos. 2010/0249155 and 2010/0168139).
CAL-101 (Idelalisib), TGR-1202, AMG-319, and INCB040093 have been reported as inhibitors of PI3Kδ and are under active clinical development. IPI-145 (duvelisib) and CAL130 have been reported to as dual inhibitors of PI3K δ/γ, IPI-145 is under clinical investigation for cancer and asthma, and for RA in combination with methotrexate.
Phosphodiesterase-4 (PDE4) inhibition is one approach to the treatment of COPD. Roflumilast, a new PDE4 inhibitor, reduces airway inflammation in COPD, as assessed with sputum neutrophil and eosinophil counts. However, roflumilast exhibits dose dependent toxicity which limits the use of roflumilast at higher doses. Calverley, P, Rabe K, et. al, Roflumilast in Symptomatic Chronic Obstructive Pulmonary Disease: Two Randomized Clinical Trials. The Lancet 2009; 374: 685-694 and Fabbri, L, Calverley, P, et. al, Roflumilast in Moderate to Severe Chronic Obstructive Pulmonary Disease Treated with Longacting Bronchodilators: Two Randomized Clinical Trials. The Lancet 2009; 374: 695-703.
In addition, Celgene has shown positive results in two phase III studies for the PDE-4 inhibitor aprelimilast in the treatment of psoriatic arthritis.
Another PDE4 inhibitor is AN2728 from Anacor Phai inaceuticals which has completed phase II studies for atopic dermatitis. Recently, Chiesi Group announced the successful completion of its Phase I trial of CHF6001, an inhaled PDE4 inhibitor being developed for the treatment of inflammatory respiratory disorders, such as chronic obstructive pulmonary disease (COPD) and asthma.
PDE4 inhibitors, however, have a narrow therapeutic window as far as efficacy and toxicity are concerned.
Despite currently available intervention therapies, improved medical treatments for autoimmune disorders, such as RA and psoriasis, and respiratory disorders, such as asthma and COPD, are still needed.
Accordingly, it is an objective of the present invention to provide new pharmaceutical compositions and methods for the treatment of respiratory and/or inflammatory diseases and conditions having enhanced activity.